Epstein-Barr virus (EBV) is a human pathogen associated with a variety of cancers, including B cell lymphomas and nasopharyngeal carcinoma. EBV encodes an oncoprotein called the latent membrane protein-1 (LMP-1) whose activity is critical for B cell transformation by EBV. The ultimate goal of the proposed research is to explore the molecular and biochemical mechanisms by which LMP-1 contributes to EBV's life cycle in vitro and then to apply results to LMP-1's potential contribution to EBV's life cycle in vivo as it relates not only to the process of tumorigenesis but to the activity of EBV in latently infected B cells of healthy individuals. LMP-1 is expressed in infected primary B cells, immortalized lypmphoblastoid cell lines, and in some tumor cell lines or biopsies. LMP-1 functions as a constitutively-active cell surface receptor and activates positive growth-regulatory signals via its intracellular C-terminal signaling domain and negative growth-regulatory signals via its transmembrane domain. The studies described in this proposal are designed with the combined goals of understanding the function of LMP-1's hydrophobic transmembrane domain in the context of a) the mechanism of LMP-1's constitutive activation of cellular growth-regulatory signaling and b) signaling resulting in negative growth-regulation. Defining the mechanism of LMP-1's constitutive activation will provide insights into the control of cellular signal transduction and may be generally applicable to the molecular mechanisms involved in normal B cell growth control and in the aberrant growth of virally and nonvirally induced malignancies. Understanding the process of negative growth-regulation by LMP-1 will provide insights into the broad areas of cell cycle regulation and cytokinesis, and may shed light on the contribution of LMP-1 to EBV's life cycle in vivo, in transformed cells and in latently infected cells in healthy seropositive individuals.